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Biomedical subjects

B Belleau

Publications and source records attributed to B Belleau.

At least 19 recordsLinked to original sources
PubMed1994

Agonist and antagonist opioid activity of axial and equatorial conformations of S-methyl- and S-allyl-morphinans.

Resolved axial (beta) and equatorial (alpha) forms of S-methyl (beta-sulforphanol, alpha-sulforphanol) and S-allyl (beta-sulfallorphan, alpha-sulfallorphan) morphinans were tested for their ability to depress the electrically evoked contractions of the guinea pig ileum and of the mouse vas deferens, to compete with the binding of prototype ligands selective for mu-, delta-, and kappa-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum and to produce analgesia in a rat thermal pain assay. beta-Sulforphanol was more potent than alpha-sulforphanol in the guinea pig ileum (relative potencies of 93% and 29% respectively, as compared with levorphanol). beta-Sulfallorphan and alpha-sulfallorphan were both inactive in the guinea pig ileum assay. In the mouse vas deferens preparation, beta-sulforphanol and alpha-sulforphanol had relative potencies of 2.1% and 1.2% as compared with levorphanol, respectively, while the S-allyl derivatives were inactive. All morphinan derivatives displayed marked binding selectivity for mu-opioid receptors but alpha-sulfallorphan also showed significant binding potency on delta-opioid receptors (12% as compared to levorphanol). The compounds were also tested for their ability to antagonize the biological activity of morphine. In the guinea pig ileum, alpha-sulfallorphan potently inhibited morphine with a Ke value of 41.7 nM. alpha-Sulforphanol also antagonized morphine but with a smaller potency (Ke = 350 nM). In the mouse vas deferens, no antagonist activity against morphine was observed with any morphinan derivative tested at 1 microM. In the rat thermal pain assay, beta-sulforphanol (intracisternally, i.c.) was more potent than alpha-sulforphanol in producing analgesia while the other morphinan derivatives were inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Neurobehavioral evidence for kappa agonist activity of the morphinan derivative 14-beta-methyl 8-oxacyclorphan [BC (3016)].

The purpose of the present study was to determine if the in vivo neurobehavioral effects of the morphinan 14-beta-methyl 8-oxacyclorphan, [BC (3016)], would reflect the kappa agonist activity found in our previous in vitro studies. The effects of intracisternal administration of various doses (10-80 micrograms) of BC (3016) on body temperature, muscle rigidity, nociception of thermal, chemical and mechanical stimuli as well as its ability to induce catalepsy were examined. The effects of intrathecal administration of the same doses of the compound on reactivity of animals to a thermal stimulus were also assessed. Finally, the ability of BC (3016) to antagonize well known neurobehavioral effects of morphine was investigated. Results indicate that the analgesic properties of BC (3016) resemble those of typical kappa agonists: Intracisternal administration of the drug failed to affect nociception to an aversive thermal stimulus but markedly reduced the reactivity of animals subjected to noxious chemical or mechanical stimuli. On the other hand, intrathecal administration of BC (3016) significantly attenuated nociception of animals to a thermal stimulus. The in vivo neurobehavioral effects of BC (3016) appear to be kappa selective since the drug did not decrease body temperature, increase muscular tone or induce catalepsy, three effects generally attributed to mu agonists. Furthermore, BC (3016) antagonized the immobility, trunk rigidity, catalepsy and analgesia induced by morphine. In summary, the present results reveal that BC (3016) displays a profile of neurobehavioral effects similar to that of well known kappa agonists.

Animals↗
PubMed1991

Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2'-deoxy-3'-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog.

We describe a novel nucleoside analog, 2'-deoxy-3'-thiacytidine (BCH-189), in which the 3' carbon of the ribose ring of 2'-deoxycytidine has been replaced by a sulfur atom. In MT-4 T cells, this compound had significant time- and dose-dependent antiviral activity against five different strains of human immunodeficiency virus type 1 (HIV-1) (mean 50% inhibitory dose, 0.73 microM); known 3'-azido-3'-deoxythymidine (AZT)-resistant HIV-1 variants did not exhibit cross-resistance to it. BCH-189 also suppressed HIV-1 replication in the U937 monocytoid cell line as well as in primary cultures of human peripheral blood mononuclear cells; in these latter systems, suppression was fuller and longer lasting than that induced by AZT. Moreover, BCH-189 was less toxic than AZT in cell culture. BCH-189 may be a promising drug for the treatment of HIV-1-associated disease.

Antiviral Agents↗
PubMed1989

Some remarkable effects of thiopeptide and derived linkages on lysozyme release from neutrophils by esters of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe-OR).

A variety of recently synthesized analogues of the chemotactic agent f-Met-Leu-Phe-OR modified in the backbone were tested for their ability to induce the release of lysozyme from human neutrophils. In sharp contrast to the effects of thiopeptide linkages on the biological activity of Leu5-enkephalin as previously reported, the presence of single thioamide bonds at either one of the endo-positions of the chemotactic peptide, abolished activity. Thioamide-derived linkages such as amidoximes and cyanamidines were generally also detrimental to activity, except in the cases of the cyanamidoformyl derivatives which showed enhanced activity and two amidoxime esters, one O-acetylated and the other O-esterified intramolecularly, which retained moderate activity. The mechanistic significance of these results is discussed in terms of conformational effects on receptor recognition.

Humans↗
PubMed1986

14-beta-Methyl-8-oxacyclorphan (BC-3016), a morphinan derivative with high affinity for kappa opioid receptor: comparison with dynorphin-A(1-13).

14-beta-Methyl-8-oxacyclorphan (BC-3016) was tested for its ability to depress the electrically evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with the binding of prototype ligands selective for kappa-, mu-, or delta-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum. BC-3016 was a very potent agonist in the GPI and MVD preparations, with ID50 of 0.7 and 31 nM, respectively. The activity of levorphanol, a standard alkaloid related to BC-3016, was much lower in both assays with ID50 values of 44 and 86 nM, respectively. Conversely, the activity of BC-3016 was quite comparable to that of dynorphin-A(1-13) in both preparations. In the GPI assay, a putative kappa-receptor antagonist, MR-2266, was 6.6 and 5.5 times more potent than naloxone in blocking the activity of BC-3016 and dynorphin-A(1-13), respectively. BC-3016 was also very potent in displacing bound [3H]ethylketocyclazocine ([3H]EKC) to membrane preparations of the guinea pig cerebellum, a brain component containing predominantly kappa-opioid receptors (Ki of 0.58 nM). Its potency in the displacement of the bound mu-ligand, 3H-labelled (D-Ala2,MePhe4,Gly-OH5)-enkephalin ([3H]DAGO), to rat brain homogenates was somewhat lower (Ki of 0.8 nM) but still high when compared with its ability to displace the delta-ligand, 3H-labelled (D-Ser2, Thr6)-Leu-enkephalin ([3H]DSLET) to rat brain homogenates (Ki of 4.45 nM). The affinity of BC-3016 for the opioid receptor was 2.1-fold higher than that of U-50488H, a selective kappa-opioid ligand.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Cyclic tetrameric clusters of chemotactic peptides as superactive activators of lysozyme release from human neutrophils.

The preparation of cyclic tetramers of formyl-methionyl-leucylphenylalanine (FMLP) amides from tetraazacycloalkanes incorporating different spacers is described. The corresponding monomeric analogs are also reported. The ability of these FMLP analogs to release lysozyme from human neutrophils was evaluated. The cyclic clusters proved to be superactive and in a manner suggestive of a cooperative response of the membrane receptors. The spasmogenicity of two prototype compounds on the guinea-pig ileum was also measured and the results briefly discussed.

Chemical Phenomena↗
PubMed1984

Synthesis and biological activity of monothionated analogs of leucine-enkephalin.

The synthesis of the four regioisomers of monothionated Leu-enkephalins (Leu-Enk) from previously reported protected precursors is described. The Tyr1-thio analog was obtained as a 1:1 mixture of the L- and D-Tyr diastereomers. The pure compounds were tested for opiate-like activity by using the guinea-pig ileum (GPI) and mouse vas deferens (MVD) preparations, by assessing analgesic effects following intra-cerebroventricular administration and by examining their ability to displace [3H]-D-Ala2, D-Leu5-enkephalin (DADLE) and [3H]-dihydromorphine from rat brain homogenates. The results demonstrate that depending on the backbone position of the thioamide function, activity can be decreased or increased. In the smooth muscle preparations as well as in the opiate binding tests, the activity of D,L-Tyr1-thio-Leu-Enk and Gly3-thio-Leu-Enk was reduced. The activity of the latter analog was also diminished in the analgesia test. In all biological assays, Phe4-thio-Leu-Enk was either equally or slightly less potent than the parent compound. However, introduction of the sulfur atom in position 2 of Leu-Enk increased the potency of the compound in all assays, the MVD assay being the most sensitive. The results are interpreted in terms of the thioamide (amide) function in receptor recognition processes, the probable behavior of thiopeptides toward physiologically relevant peptidases and the structural divergences between tissue-specific receptors.

Amino Acids, Sulfur↗
PubMed1982

Inhibition by the tetramine disulphide, benextramine, of cardiac chronotropic histamine H2-receptor-mediated effects.

1 Benextramine (N,N1-bis[o-methoxybenzylamino)-n-hexyl]cystamine), which irreversibly blocks alpha-adrenoceptors and does not inhibit the H1-receptor-mediated contractile effect of histamine on guinea-pig isolated ileum, also did not inhibit the H1-receptor-mediated inotropic effect of histamine on guinea-pig isolated atrium. 2 Benextramine irreversibly inhibited the H2-receptor-mediated chronotropic effect of histamine on guinea-pig isolated atrium. 3 Since its combination with the competitive H2-receptor blocking drug cimetidine had a additive blocking effect, benextramine appears to act directly on the chronotropic H2-receptor.

Adrenergic alpha-Antagonists↗
PubMed1982

Presynaptic effect of clonidine antagonized by the tetramine disulphide, benextramine.

1 The presynaptic alpha-adrenoceptor blocking activity of the newly synthesized alpha-adrenoceptor blocking drug, benextramine, was evaluated in the isolated left atrium of the guinea-pig heart. 2 High-voltage stimulation increased the force of contraction of electrically driven atrial strips, presumably by releasing noradrenaline from sympathetic nerve endings. Like phentolamine, benextramine increased the effect of high-voltage stimulation, presumably by blocking presynaptic alpha-adrenoceptors. 3 Clonidine reduced the effect of high-voltage stimulation, presumably by stimulating presynaptic alpha-adrenoceptors. The inhibitory effect of clonidine was antagonized noncompetitively by benextramine and competitively by phentolamine. 4 Combined administration of benextramine and phentolamine only resulted in the competitive phentolamine antagonism. Thus phentolamine protected the presynaptic alpha-adrenoceptors against benextramine blockade.

Adrenergic alpha-Antagonists↗
PubMed1982

Inhibition of adrenaline-induced platelet aggregation by the alpha-adrenoceptor blocking drug benextramine.

1 The activity of the irreversible alpha-adrenoceptor blocking drug, benextramine, was determined in human platelets. 2 Compared to its postsynaptic and presynaptic alpha-adrenoceptor blocking potency, benextramine had a very low potency as an antagonist of adrenaline-induced platelet aggregation. 3 The results confirm the previous observation with the irreversible alpha-adrenoceptor blocking drug, phenoxybenzamine, that platelet alpha-adrenoceptors differ from postsynaptic and presynaptic alpha-adrenoceptors.

Adenosine Diphosphate↗
PubMed1981

An investigation of the destruction of the beta-lactam ring of penems by the albumin drug-binding site.

The plasma proteins have been reported to exert irreversible effects on some beta-lactams. The penems represent a class of antibiotics of great interest due to their wide spectrum of activity. However, many compounds of this class were found to be unstable in rat serum. A prototype compound, (+/-)-2-methylpenem-3-carboxylic acid (BCL-98), was selected for detailed investigations. The capacity of penems to inhibit the destruction of a chromogenic beta-lactam (BCL-604) by serum was the technique selected to study the interaction of BCL-98 with serum proteins at the specific destructive site. The serum of various species was investigated and the magnitude of BCL-604 destruction was in the following order: rat = human greater than dog greater than mice. The human plasma proteins were fractionated on a Sephadex column and the fractions tested individually. The albumin fraction was found to be entirely responsible for the destruction, the globulin fractions being completely inactive. The reaction of Ellman's reagent with serum as not diminished in the presence of the BCL-98, thus demonstrating that the sulfhydryl group of albumin is not involved in this binding. Displacement of a fluorescent probe (5-dimethylaminonaphthalene-1-sulfonamide) by BCL-98 showed that the binding site for the latter is the same as the one occupied by L-tryptophan and thus involves the epsilon-lysine amino group of the albumin binding site. The exact nature of this binding is not yet established, but it can be inferred that it may involve acylation of the epsilon-lysine group at the binding site. Some analogs of BCL-98 were also investigated. The basic functionality seems to protect the molecule from the destructive site of the albumin, probably because this substituent induces binding at another nondestructive site resulting in a prolonged half-life in the blood.

Animals↗
PubMed1980

Potentiation and inhibition of nicotinic effects on striated muscle by the tetramine disulfide benextramine.

In low concentrations (0.3-3 muM) the tetramine disulfide benextramine (BHC; N,N'-bis[6-(o-methoxybenzylamino)-n-hexyl]cystamine) potentiated the contracture of the isolated frog rectus abdominis muscle caused by acetylcholine but in the presence of physostigmine or in a higher concentration (10 muM) it inhibited. Benextramine only inhibited the contracture caused by carbachol or butyrylcholine. The all-carbon analog of benextramine only inhibited the effect of acetylcholine. The inhibitory effects of benextramine and its carbon analog were noncompetitive and readily reversible but the potentiating effect of benextramine was not readily reversible.

Acetylcholine↗
PubMed1980

Irreversible alpha adrenoceptor blocking effects and reversible muscarinic blocking and nicotinic blocking effects of tetramine disulfides on the heart.

Inotropic effects of phenylephrine, carbachol, and butyrylcholine were used in the rabbit left atrium to evaluate respectively alpha adrenoceptor blocking, muscarinic blocking, and nicotinic blocking effects of tetramine disulfides ((RNH(CH2)nNH(CH2)2S-)2 x 4HX). The alpha adrenoceptor blocking potencies of newly synthesized derivatives R = 3',4'-(OH)2-benzyl, n = 5-9, were similar to those of compounds R = 2'-OCH2-benzyl, n = 5-7. Muscarinic blocking and nicotinic blocking potencies of tetramine disulfides were correlated with alpha adrenoceptor blocking potency. Compounds R = 3',4'-(OH)2-benzyl had relatively low muscarinic blocking potencies and compounds R = 2'-OCH3-benzyl had relatively low nicotinic blocking potencies.

Adrenergic alpha-Antagonists↗
PubMed1980

Reactivation by cysteamine of vascular alpha adrenoceptors blocked by the tetramine disulfide benextramine and interaction of benextramine with phenoxybenzamine.

The tetramine disulfide benextramine irreversibly blocked the noradrenaline-induced contraction of the isolated rabbit aorta in a manner similar to that observed with phenoxybenzamine. Cysteamine abolished the benextramine blockade but not the phenoxybenzamine blockade. Incubation of aortic tissue with benextramine prior to phenoxybenzamine exposure and followed by cysteamine treatment led to a recovery of the noradrenaline response that depended on the dose of benextramine. Thus benextramine protected the alpha adrenoceptors against phenoxybenzamine blockade.

Animals↗
PubMed1979

Cardiac muscarinic blocking and atropinic blocking effects of a tetramine disulfide and alpha-adrenoceptor blocking activity.

Since many alpha-adrenoceptor blocking drugs were known to have muscarinic blocking activity, BHC, a newly synthesized tetramine disulfide with alpha-adrenoceptor blocking activity, and two of its analogs were tested for muscarinic blocking activity in the isolated guinea pig atrium and ileum. BHC had muscarinic blocking activity. Its potency was higher in the atrium than in the ileum. The cardiac muscarinic blocking potency of the analog that contained carbon atoms instead of sulfur atoms was similar to that of BHC. Lower concentrations of the drugs antagonized inotropic effects of acetylcholine competitively, but higher concentrations had a smaller effect than expected for competitive antagonism. In the atrium BHC competitively inhibited the muscarinic blocking effect of atropine. Its atropinic blocking potency was similar to the muscarinic blocking potency. Quinidine and gallamine also had muscarinic blocking and atropinic blocking effects in the atrium but were about 10 times less potent than BHC.

Adrenergic alpha-Antagonists↗
PubMed1979

Inhibition of the cardiac inotropic effect of phenylephrine by a tetramine disulfide with irreversible alpha-adrenoceptor blocking activity.

The newly synthesized alpha-adrenoceptor blocking drug BHC (N,N'-bis[6-(10-methoxybenzyl-amino)-a-hexyl]cystamine) was found to block irreversibly the positive inotropic effect of the sympathomimetic drug phenylephrine on the isolated rat left atrium. BHC was used to test the adrenoceptor interconversion hypothesis which claims that low temperature converts inotropic beta-adrenoceptors in rat atrium and frog ventricle to alpha-adrenoceptors. There was no evidence of adrenoceptor 'interconversion.' In the rat atrium low temperature did not increase the BHC antagonism of phenylephrine and did not cause BHC to inhibit the inotropic effect of noradrenaline or isoprenaline. In the perfused frog heart low temperature did not lead BHC to inhibit the inotropic effect of phenylephrine, adrenaline, or isoprenaline.

Adrenergic alpha-Antagonists↗